Chronic kidney disease (CKD) prevalence is increasing rapidly and fracture incidence is much higher in patients with CKD than in the general population. Unfortunately, fracture risk prediction by dual energy X-ray absorptiometry (DXA) is poorer among CKD patients than in the general population and improved imaging methods are necessary to evaluate their fracture susceptibility. Ultra high resolution peripheral quantitative computed tomography (HRpQCT; resolution 80-100 um) is a novel technology that characterizes both cortical and trabecular microarchitecture. Finite element analysis (FEA), a measure of bone strength, can be applied to HRpQCT data sets. The hypotheses of this application are that CKD stages 3 to 5 are associated with progressive alterations in trabecular and cortical microarchitecture that reduce strength and increase fracture susceptibility, and HRpQCT with FEA, will provide greater fracture discrimination than DXA in patients with CKD. We will test this hypothesis in a cross-sectional study of 150 subjects with CKD stages 3 to 5 (75 with fracture). In a subset, we will validate HRpQCT measurements, established and novel markers of bone turnover against histomorphometry of transiliac bone biopsies. In CKD stage 4 subjects (n=50) we will longitudinally evaluate bone microarchitecure in relation to changes in kidney function. This study is highly relevant to public health, as fracture risk and its associated morbidity and mortality are exceedingly high in CKD patients and CKD and osteoporosis are highly coprevalent. This project also forms the training platform of my 5-year career development plan, the goal of which is to allow me to become an independent clinical investigator in the field of CKD-mineral and bone disorders (MBD). The plan includes didactic training in radiographic imaging, advanced biostatistics and epidemiological methods, specific hands-on training in HRpQCT, FEA and quantitative histomorphometry of transiliac bone biopsies with leading experts in the fields of bone biomechanics and bone cell biology, and frequent meetings with my mentor and co-mentor, leaders in the field of metabolic bone disease and CKD-MBD. During the award, I will develop expertise in using these tools to assess bone strength in CKD patients. In the fourth year, I will begin planning an RO1 submission. The skills and knowledge I acquire during this award will allow me to develop into a productive, independent investigator with a skill set that is unusual in the fields of nephrology and endocrinology. PUBLIC HEALTH RELEVANCE: This study is highly relevant to public health, as fracture risk and its associated morbidity and mortality are exceedingly high in CKD patients and CKD and osteoporosis are highly coprevalent.